1. Technical Field
The present invention relates, in general, to desensitization, and, in particular, to a method of inhibiting agonist-specific desensitization, to compounds suitable for use in such a method and to pharmaceutical compositions comprising same.
2. Background Information
Desensitization is a general phenomenon which is characterized by a reduced responsiveness following prolonged exposure to a hormone or drug. Occupancy of a wide variety of hormone and neurotransmitter receptors by agonists often leads to desensitization, that is, to a loss of receptor responsiveness to subsequent stimulation by agonist. This particular phenomenon is generally termed homologous desensitization. This is in contrast to the heterologous form of desensitization, which is defined as a loss of receptor responsiveness caused by agonist occupancy of other receptors.
Homologous desensitization has been most thoroughly studied for the .beta.-adrenergic receptor (.beta.AR)-adenylyl cyclase system (Benovic et al (1988) Ann. Rev. Cell Biol. 4:405-428). Homologous desensitization of .beta.ARs is accompanied by receptor phosphorylation (Sibley et al (1985) J. Biol. Chem. 260:3883-3886; Strasser et al (1986) Biochemistry 25:1371-1377). A cAMP-independent kinase, termed .beta.AR kinase, has been described that specifically phosphorylates the agonist-occupied forms of the .beta..sub.2 -adrenergic receptor (.beta..sub.2 AR) and .alpha..sub.2 -adrenergic receptor (Benovic et al (1986) Proc. Natl. Acad. Sci. USA 83:2797-2801; Benovic et al (1987) J. Biol. Chem. 262:17251-17253) as well as light-activated rhodopsin (Benovic et al (1986) Nature (London) 322:867-872). Phosphorylation of the .beta..sub.2 AR by .beta.AR kinase may trigger the process of functional uncoupling from the stimulatory guanine nucleotide binding protein, G.sub.s (Benovic et al (1987) Proc. Natl. Acad. Sci. USA 84:8879-8882).
While there have been several publications involving attempts at blocking desensitization (Mallorga et al (1980) Proc. Natl. Acad. Sci. USA 77:1341-1345; Shima et al (1983) J. Biol. Chem. 258:2083-2086; Heyworth et al (1984) Biochem. J. 222:189-194; Fano et al (1986) J. Auton. Pharmacol. 6:47-51; DeBernardi et al (1987) Proc. Natl. Acad. Sci. USA 84:2246-2250; and Toews (1987) Mol. Pharmacol. 32:737-742), none of these studies directly demonstrates the inhibition of agonist-specific desensitization. Moreover, none of the compounds utilized in these studies directly inhibit the .beta.AR kinase. The identification of compounds which specifically inhibit this kinase could provide a method of inhibiting desensitization. The inhibition of desensitization should result in enhanced and prolonged receptor action in response to endogenous compounds and drugs. In the case of drugs, this means increased drug efficacy leading to the use of lower drug doses, and reduced side effects. In addition, it should allow prolonged treatment with drugs.